Neuromyelitis Optica (NMO) is a rare autoimmune inflammatory disease that affects the spinal cord and optical nerves leading to limb paralysis and loss of vision. Despite advances in the understanding of underlying disease mechanisms and patient diagnostic criteria there is a lack of treatment options. A specific cellular component of NMO disease was found to be neutrophils as they play a pathogenic role in causing the observed inflammation. We propose targeting a recently discovered pathogenic mediator secreted by neutrophils in NMO disease by using inhibitors of neutrophil elastase as a therapeutic approach. Various neutrophil elastase inhibitors have been used for other indications and our strategy seeks to re-purpose these drugs for NMO to find an optimal therapeutic. Our first aim will test the efficacy of two neutrophil elastase inhibitors using a Th1 mouse EAE transfer model that recapitulates the pathogenic features seen in NMO patients. We will measure therapeutic effect by EAE disease scoring and blood will be collected to assess levels of serum neutrophil elastase and other serine proteases, cytokines, and chemokines for potential biomarkers. Spinal cord and optical tract will also be harvested for histology to assess cellular infiltration. Our second aim builds upon the first by using the identified optimal candidae therapeutic in combinatorial studies with current NMO standard of care methylprednisolone. These studies will again use the Th17 mouse EAE transfer model to measure efficacy and will specifically test for synergistic therapeutic effect using the combination of drugs. Blood will agan be collected for serum biomarker analysis and spinal cord and optical tract for histology. The overall goal of these studies is to re-purpose a neutrophil elastase inhibitor as a novel therapeutic for NMO whether as stand-alone or add-on combinatorial therapy. This Phase I proposal seeks to demonstrate proof of efficacy and prepares the project for additional research and pre-clinical studies in Phase II as well as potential research collaboration joint ventures wit interested pharmaceutical companies.